Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature.

BACKGROUND: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. METHODS: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). RESULTS: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. CONCLUSIONS: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.

Hybrid immunity expands the functional humoral footprint of both mRNA and vector-based SARS-CoV-2 vaccines

Despite the successes of current COVID-19 vaccines, waning immunity, the emergence of variants of concern, and breakthrough infections among vaccinees, have begun to highlight opportunities to improve vaccine platforms. Real-world vaccine efficacy studies have highlighted the reduced risk of breakthrough infection and disease among individuals infected and vaccinated, referred to as hybrid immunity. Thus, we sought to define whether hybrid immunity shapes the humoral immune response to SARS-CoV-2 following Pfizer/BNT162b2, Moderna mRNA1273, ChadOx1/AZ1222, and Ad26.COV2.S vaccination. Each vaccine exhibits a unique functional humoral profile in vaccination only or hybrid immunity. However, hybrid immunity shows a unique augmentation of S2-domain-specific functional immunity that was poorly induced for the vaccination only. These data highlight the importance of natural infection in breaking the immunodominance away from the evolutionarily unstable S1-domain and potentially affording enhanced cross-variant protection by targeting the more highly conserved S2 domain of SARS-CoV-2. Graphical Kaplonek et al shows that mRNA- and vector-based SARS-CoV-2 vaccines display distinct immune profiles in individual vaccinated only or infected and vaccinated. The infection prior vaccination helps improving the immunity and triggers response to the more conserve domain of SARS-CoV-2 which might enhance the effectiveness of vaccines against new variants.

SARS-CoV-2 seroprevalence among children in Latvia: A cross-sectional study

Coronavirus disease 2019 (COVID-19) is a major global health concern. In contrast to adults, the course of the disease has been observed to be mild or even asymptomatic in children. It is therefore both clinically and epidemiologically important to measure the seroprevalence in children and adolescents to discern the overall morbidity of the disease and to compare these findings with similar data collected globally. We conducted a cross-sectional study between March and July of 2022 at the Children Clinical University Hospital in Riga, Latvia, to evaluate the seroprevalence of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Participants aged 0 to 18 years were enrolled during hospitalization for reasons other than COVID-19. The levels of SARS-CoV-2 spike protein and nucleocapsid antibodies were measured in blood samples. The possibility of transplacental antibody transport was evaluated by directly interviewing the mothers of participants aged 18 months and younger. Various demographic and epidemiological risk factors and their association with seroprevalence were analyzed. Positive SARS-CoV-2 nucleocapsid antibodies were designated the main criterion for seropositivity. Of 200 enrolled children, 173 were found to be seropositive, resulting in an overall seroprevalence of 86.5%. The highest seroprevalence was detected in children and adolescents aged 12 to 18 years. With the progression of the COVID-19 pandemic, the seroprevalence in children has increased significantly. We found that almost 1-third of seropositive children in our study population were unaware of being previously infected with SARS-CoV-2 due to an asymptomatic course of the disease. Our study findings pertaining to high seropositivity among children and adolescents might be beneficial for public authorities to adapt epidemiological strategies and prevention measures. The high seroprevalence rate reported here and in many other populations around the world suggests that COVID-19 will likely become one of the many seasonal viral infections.

SARS-CoV-2 seroprevalence among children in Latvia: A cross-sectional study.

Coronavirus disease 2019 (COVID-19) is a major global health concern. In contrast to adults, the course of the disease has been observed to be mild or even asymptomatic in children. It is therefore both clinically and epidemiologically important to measure the seroprevalence in children and adolescents to discern the overall morbidity of the disease and to compare these findings with similar data collected globally. We conducted a cross-sectional study between March and July of 2022 at the Children Clinical University Hospital in Riga, Latvia, to evaluate the seroprevalence of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Participants aged 0 to 18 years were enrolled during hospitalization for reasons other than COVID-19. The levels of SARS-CoV-2 spike protein and nucleocapsid antibodies were measured in blood samples. The possibility of transplacental antibody transport was evaluated by directly interviewing the mothers of participants aged 18 months and younger. Various demographic and epidemiological risk factors and their association with seroprevalence were analyzed. Positive SARS-CoV-2 nucleocapsid antibodies were designated the main criterion for seropositivity. Of 200 enrolled children, 173 were found to be seropositive, resulting in an overall seroprevalence of 86.5%. The highest seroprevalence was detected in children and adolescents aged 12 to 18 years. With the progression of the COVID-19 pandemic, the seroprevalence in children has increased significantly. We found that almost 1-third of seropositive children in our study population were unaware of being previously infected with SARS-CoV-2 due to an asymptomatic course of the disease. Our study findings pertaining to high seropositivity among children and adolescents might be beneficial for public authorities to adapt epidemiological strategies and prevention measures. The high seroprevalence rate reported here and in many other populations around the world suggests that COVID-19 will likely become one of the many seasonal viral infections.

SARS-CoV-2 mRNA vaccination elicits robust antibody responses in children.

Although children have been largely spared from coronavirus disease 2019 (COVID-19), the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) with increased transmissibility, combined with fluctuating mask mandates and school reopenings, has led to increased infections and disease among children. Thus, there is an urgent need to roll out COVID-19 vaccines to children of all ages. However, whether children respond equivalently to adults to mRNA vaccines and whether dosing will elicit optimal immunity remain unclear. Here, we aimed to deeply profile the vaccine-induced humoral immune response in 6- to 11-year-old children receiving either a pediatric (50 µg) or adult (100 µg) dose of the mRNA-1273 vaccine and to compare these responses to vaccinated adults, infected children, and children who experienced multisystem inflammatory syndrome in children (MIS-C). Children elicited an IgG-dominant vaccine-induced immune response, surpassing adults at a matched 100-µg dose but more variable immunity at a 50-µg dose. Irrespective of titer, children generated antibodies with enhanced Fc receptor binding capacity. Moreover, like adults, children generated cross-VOC humoral immunity, marked by a decline of omicron-specific receptor binding domain, but robustly preserved omicron spike protein binding. Fc receptor binding capabilities were also preserved in a dose-dependent manner. These data indicate that both the 50- and 100-µg doses of mRNA vaccination in children elicit robust cross-VOC antibody responses and that 100-µg doses in children result in highly preserved omicron-specific functional humoral immunity.

Towards a population-based threshold of protection for COVID-19 vaccines.

Correlates of protection for COVID-19 vaccines are urgently needed to license additional vaccines. We measured immune responses to four COVID-19 vaccines of proven efficacy using a single serological platform. IgG anti-Spike antibodies were highly correlated with ID50 neutralization in a validated pseudoviral assay and correlated significantly with efficacies for protection against infection with wild-type, alpha and delta variant SARS-CoV-2 virus. The protective threshold for each vaccine was calculated for IgG anti-Spike antibody. The mean protective threshold for all vaccine studies for WT virus was 154 BAU/ml (95 %CI 42-559), and for studies with antibody distributions that enabled precise estimation of thresholds (i.e. leaving out 2-dose mRNA regimens) was 60 BAU/ml (95 %CI 35-102). We propose that the proportion of individuals with responses above the appropriate protective threshold together with the geometric mean concentration can be used in comparative non-inferiority studies with licensed vaccines to ensure that new vaccines will be efficacious.